Project Summary Caloric restriction (CR), undernutrition without malnutrition, offers a powerful way to explore mechanisms of delayed aging. CR is the only environmental intervention that repeatedly and strongly increases maximum lifespan and delays biological aging in laboratory rodents. The rhesus monkey provides an extremely valuable model in which to test the ability of CR to extended healthspan and lifespan in a primate species. By proving that CR extends healthspan and lifespan in rhesus monkeys we have validated an outstanding model for physiological, systemic, and molecular aging studies that is directly translational to human aging. In 1989, we began a study to test the overall hypothesis that adult-onset CR could slow the aging process in a primate species. Importantly, these studies are not yet complete as 17% of the monkeys are alive. Thus, the major goals of this application are active data collection from remaining animals, integrative longitudinal analysis of 25+ years of study data, and expansion of studies into the mechanisms of CR. There has been renewed emphasis in biology and medical research on the impact of adiposity in health and disease vulnerability. Our preliminary molecular profiling data demonstrate that adipose tissues respond to aging and CR in a manner that is not simply reflective of adiposity. We will test the hypothesis that adipose tissue contributes to age- related disease vulnerability and its prevention by CR in a depot specific manner in nonhuman primates. We propose two Specific Aims: 1) To perform and facilitate in-depth, longitudinal analyses of the biology of aging and effects of moderate (30%) adult-onset CR in a primate species. Health, biometric and clinical measures of the long-term CR study animals will be conducted to ultimately determine the effects of CR on maximal lifespan. Data will be combined to create an integrative perspective on health outcomes in response to CR. All data and the inventory of available tissues will be made available through a newly created curated online accessible database to extend studies on aging and the mechanisms of CR to a broad collaborative research network. 2) To determine the adipose tissue depot specific response to age and CR. We will determine the signature of age and CR through high resolution molecular profiling, elucidate the contribution of adipose tissue to lipid and metabolite profiles in serum, and identify novel systemic indices of health status with potential clinical value. Using banked specimens of subcutaneous and visceral (mesenteric) adipose tissues (44 males and females, median age 26 years, age range: 13-33 years), we propose to derive the molecular signature of CR in terms of metabolomics, lipidomics, and transcriptomics, and use these data to identify depot specific processes and pathways associated with the enhanced resilience to age-related disease conferred by CR. This study will advance biology of aging research by defining fully the influence of CR on maximal lifespan under tightly controlled conditions in a long-lived primate species, and provide unparalleled mechanistic insights into age-related disease vulnerability in this highly translatable model.